Heart failure (HF) remains a leading cause of death in Western countries and the development of new therapeutic agents for HF has been challenged. The recent major advances in the understanding of molecular signaling in the cardiac myocytes under the pathological stress has suggested the way for different approaches to treating heart disease, in particular to regulate intrinsic targets on the intracellular side. The calcium-transporting ATPase ATP2A2 (SERCA2a) is ATPase responsible for Ca2+ re-uptake during excitation-contraction coupling. A characteristic of heart failure is impaired Ca2+ uptake resulting from decreased expression and reduced activity of SERCA2a. To this end, restoration of SERCA2a expression by gene transfer can be effective in improving cardiac function in animal models and heart-failure patients. It was found that the levels and activity of SERCA2a in cardiac myocytes are modulated by small ubiquitin-like modifier type 1 (SUMO I)-mediated unique post-translational modification (PTM), named SUMOylation (Kho C, Lee A, Jeong D, Oh J G, Chaanine A H, Kizana E, Park W J, Hajjar R J, “SUMO1-dependent modulation of SERCA2a in heart failure”, Nature 2011 Sep. 7; 477(7366):601-5). SERCA2a is SUMOYLated by SUMO1 at two specific sites Lysine 480 and 585. The levels of SUMO1 and the SUMOylation of SERCA2a itself were greatly reduced in failing hearts. SUMO1 restitution by adeno-associated-virus-mediated gene delivery maintained the protein abundance of SERCA2a and markedly improved cardiac function in mice with heart failure. This effect was comparable to SERCA2A gene delivery. Since it has been shown that SUMO1 enhances the stability and the ATPase activity of SERCA2a, its decrease causes further dysfunction of SERCA2a and further worsening of dysfunction. Further, gain of function experiments by transgenesis and gene therapy showed that SUMO1 gene therapy rescues contractile function and improves mortality in models of heart failure. To this end, there is a need to develop new small molecules that increase SERCA2a SUMOylation, which are useful for treating HF.
Further, induction of SUMOylation has also been implicated in the treatment of cancer (Kira Bettermann, Martin Benesch, Serge Weis, Johannes Haybaeck. SUMOylation in carcinogenesis. Cancer Letters (2012) 316, 113-125), neurodegenerative disorders such as Huntington's disease (Steffan, J. S. et al. SUMO modification of Huntingtin and Huntington's disease pathology. Science (2004) 304, 100-104), Parkinson's disease (Dorval, V., Fraser, P. E. Small ubiquitin-like modifier (SUMO) modification of natively unfolded proteins tau and a-synuclein. J. Biol. Chem. (2006) 281, 9919-9924), Alzheimer's disease (Zhang, Y. Q. and Sarge, K. D. Sumoylation of amyloid precursor protein negatively regulates Ab aggregate levels. (2008) Biochem. Biophys. Res. Commun. 374, 673-678), and amyotrophic lateral sclerosis (ALS) (Fei, E. et al. SUMO-1 modification increases human SOD1 stability and aggregation. Biochem. Biophys. Res. Commun. (2006) 347, 406-412), viral and bacterial infection (Békés M, Drag M. Trojan horse strategies used by pathogens to influence the small ubiquitin-like modifier (SUMO) system of host eukaryotic cells. J Innate Immun. (2012) 4, 159-67), liver disease (Guo W H, Yuan L H, Xiao Z H, Liu D, Zhang J X. Overexpression of SUMO-1 in hepatocellular carcinoma: a latent target for diagnosis and therapy of hepatoma. J Cancer Res Clin Oncol. (2011) 137, 533-41), and inflammation (Pascual G, Fong A L., Ogawa S, Gamliel A, Li A C, Perissi V, Rose D W, Willson T M, Rosenfeld M G, Glass C K. A SUMOylation-dependent pathway mediates transrepression of inflammatory response genes by PPAR-gamma. Nature (2005) 437, 759-63).
To this end, there is a need to develop new small molecules that increase SERCA2a SUMOylation, which are useful for treating HF. This application addresses this need and others.